Mapping the Theories of Preeclampsia and the Role of Angiogenic Factors

Harvard University, Cambridge, Massachusetts, United States
Obstetrics and Gynecology (Impact Factor: 5.18). 02/2007; 109(1):168-80. DOI: 10.1097/01.AOG.0000249609.04831.7c
Source: PubMed


To evaluate claims that elevated soluble fms-like tyrosine kinase-1 receptor (sFlt-1) and decreased placental growth factor predict preeclampsia.
MEDLINE (1966-March 2006), EMBASE (1980-June 2006), POPLINE (1980-June 2006), CINAHL (1982-June 2006), and LILACS (1982-June 2006) were searched, and experts contacted.
Studies identified and included were those reporting blood and urine levels of sFlt-1 or placental growth factor obtained before gestational week 30 or overt preeclampsia.
Ten of 184 available studies analyzing sFlt-1 and 14 of 319 studies analyzing placental growth factor were included in this review. There was considerable interreport heterogeneity in methodology and results for sFlt-1 measured before gestational week 25. After week 25 placental growth factor and sFlt-1 levels varied consistently between the normal pregnancy group and women destined to develop preeclampsia, achieving significance in women who developed severe preeclampsia.
Third-trimester increases in sFlt-1 and decreases in placental growth factor levels are associated with preeclampsia, specifically severe disease, based on retrospective data. The evidence is insufficient to recommend these markers to be used for screening, and prospective studies employing rigorous laboratory and study design criteria are needed to determine the clinical usefulness of these tests.

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    • "The results from these experiment correlate with the findings shown in cells in where the treated group developed PE-like symptoms, significant hypertension and heavy albuminuria and downregulation of PlGF (Maynard et al., 2003). Despite all these recent findings the genesis of ED in PE still an enigma (Nagamatsu et al., 2004; Widmer et al., 2007). However, recently, another interesting study explored the effects of hypoxia on the regulation of VEGF, PlGF, and sFlt-1, in isolated cytotrophoblasts , HUVECs and villous fibroblasts. "
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    ABSTRACT: Preeclampsia (PE) is an often fatal pathology characterized by hypertension and proteinuria at the 20th week of gestation that affects 5-10% of the pregnancies. The problem is particularly important in developing countries in where the incidence of hypertensive disorders of pregnancy is higher and maternal mortality rates are 20 times higher than those reported in developed countries. Risk factors for the development of PE include obesity, insulin resistance and hyperlipidemia that stimulate inflammatory cytokine release and oxidative stress leading to endothelial dysfunction (ED). However, how all these clinical manifestations concur to develop PE is still not very well understood. The related poor trophoblast invasion and uteroplacental artery remodeling described in PE, increases reactive oxygen species (ROS), hypoxia and ED. Here we aim to review current literature from research showing the interplay between oxidative stress, ED and PE to the outcomes of current clinical trials aiming to prevent PE with antioxidant supplementation.
    Full-text · Article · Oct 2014 · Frontiers in Physiology
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    • "Preeclampsia remains one of the major causes of maternal and neonatal morbidity worldwide, affecting up to 5–8% of pregnant women (Turner, 2010). Preeclampsia is considered a " disease of theories " , in which a wide spectrum of explanations has been put forward, proposing a range of molecular and environmental causes (Widmer et al., 2007; Mignini et al., 2006). It is characterized by an abnormal vascular response to placentation that is associated with endothelial cell dysfunction and systemic vascular resistance (Robillard et al., 2009). "
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    ABSTRACT: Preeclampsia involves an exacerbated maternal inflammatory response that suggests a possible role of innate immunity. NK cells can promote this kind of response through cytokine production and the expression of activating or inhibitory receptors. The aims of the present study were to explore cytokine production by peripheral blood mononuclear cells, as well as cytotoxic ability and receptor expression for HLA-E and HLA-G molecules in peripheral natural killer (NK) cells of women with early-onset severe preeclampsia without HELLP (hemolysis, elevated liver enzyme levels and a low platelet count) syndrome. The expression of the ILT2, KIRDL4, NKG2A, and NKG2C receptors and of cytotoxic activity was measured in non-stimulated NK cells, whereas the intracellular expression of IL-4, IL-10, IL-13, IL-12, IFNγ, TNF and VEGF, was assessed in non-stimulated peripheral blood mononuclear cells subsets using flow cytometry. Circulating soluble HLA-G was also determined by ELISA. The intracellular cytokines tested were significantly higher in NK cell subsets from severely preeclamptic women compared with the control group. On the other hand, the percentage of NK cells expressing NKG2A or NKG2C and the cytotoxic activity of NK cells were significantly higher in severely preeclamptic women. Furthermore, there was a significant correlation between urine protein concentration and soluble human leukocyte antigen G (soluble HLA-G) in serum. We conclude that patients with early-onset severe preeclampsia without HELLP syndrome have increased NK cell function related to cytokine production, cytotoxicity and expression of lectin-like receptors such as NKG2.
    Full-text · Article · Feb 2013 · Journal of Reproductive Immunology
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    • "The angiogenic growth factors vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are important for placental development and angiogenesis, whereas soluble fms-like tyrosine kinase 1 (sFlt-1) binds to these proteins and thereby inhibits their activity. Previous studies have demonstrated elevated blood sFlt-1 levels or reduced blood PlGF levels in women whose pregnancies were complicated by intrauterine growth restriction, preeclampsia, and gestational hypertension (Asvold et al. 2011; Levine et al. 2004; Smith et al. 2007; Thadhani et al. 2004), and in infants of mothers with preeclampsia (Catarino et al. 2009; Staff et al. 2005); but other studies reported no associations or associations in the opposite direction (Asvold et al. 2011; Jacobs et al. 2011; Smith et al. 2007; Thadhani et al. 2004; Widmer et al. 2007). In addition, indices of placental vascular resistance and the presence of uterine artery notching (an abnormality of the Doppler ultrasound waveform that indicates increased blood flow resistance) have been used to identify complicated pregnancies (Cnossen et al. 2008; Schlembach et al. 2007). "
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    ABSTRACT: Background: Air pollution exposure during pregnancy might affect placental growth and function, perhaps leading to pregnancy complications. Objective: We prospectively evaluated the associations of maternal air pollution exposure with markers of placental growth and function among 7,801 pregnant women in the Netherlands. Methods: We estimated levels of particulate matter ≤ 10 µm in aerodynamic diameter (PM10) and nitrogen dioxide (NO2) at the home address for different periods during pregnancy using dispersion modeling techniques. Pro- and anti-angiogenic factors [placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1), respectively] were measured in first- and second-trimester maternal blood and in fetal cord blood samples at delivery. Pulsatility index of the uterine and umbilical arteries was measured by Doppler ultrasound in second and third trimester, and notching was assessed in third trimester. Placenta weight and birth weight were obtained from medical records. Results: Higher PM10 and NO2 exposure levels were associated with lower second-trimester maternal sFlt-1 and PlGF levels. PM10 and NO2 exposures averaged over total pregnancy were associated with higher sFlt-1 and lower PlGF levels in fetal cord blood, consistent with an anti-angiogenic state. PM10 and NO2 exposures were not consistently associated with second- or third-trimester placental resistance indices. NO2 exposure was associated with third-trimester notching (odds ratio 1.33; 95% CI: 0.99, 1.78 per 10-µg/m3 increase in the prior 2 months). PM10 and NO2 exposures were associated with lower placenta weight (–11.8 g; 95% CI: –20.9, –2.7, and –10.7 g; 95% CI: –19.0, –2.4, respectively, per 10-µg/m3 increase in the prior 2 months), but not with placenta to birth weight ratio. Conclusions: Our results suggest that maternal air pollution exposure may influence markers of placental growth and function. Future studies are needed to confirm these findings and explore the maternal and fetal consequences.
    Full-text · Article · Aug 2012 · Environmental Health Perspectives
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